The goal of this research project is to define the structure and radioactive label for ligands that will per-mit quantitative measurement of amyloid sites in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. A radiotracer that bound specifically to amyloid would be of great utility in diagnosis, monitoring treatment, and research of such Alzheimer's disease and related gerontological disorders. Based on preliminary in vitro binding results using a classical structure-activity relationship approach, we found that certain benzoxazole derivatives showed affinity to amyloid protein in the nanomolar range. In this application we propose to test the following hypotheses: 1) Novel Indole and benzimidazole derivatives with appropriately functionalized aromatic substituents will favor binding to amyloid Ab(1-40) protein; and 2) radio-labeling with PET or SPECT radionuclides will provide a molecular probe that can image amyloid protein in vivo. Specifically, this project poses the following specific aims AIM #1. Measure binding to amyloid protein of a group of benzothiazole derivatives already synthesized to expand the structure-activity relationship in this class of compounds. Nine candidates will be tested by in vitro homogenate displacement binding against radiolabeled ligand for amyloid protein. AIM #2. Synthesize a defined library of halogenated heterocyclic analogs and screen for binding to amyloid protein. The working hypothesis is that the successful structure will incorporate the elements of an electron-donating group on an aromatic ring (A) attached to an aromatic heterocyclic 5/6 ring system (B/C). Eleven candidates will be synthesized and tested by in vitro homogenate displacement binding against radiolabeled ligand for amyloid protein. AIM #3. Radiolabel the best candidates with radioactive I-123 or F-18 and determine their in vivo uptake properties in nonhuman primates. The candidates with binding affinities better than 10 nM will be radiolabeled and their lipophilicity will be measured as the octanol-buffer partition coefficient (log D). Compounds with log D less than 3.5 will be studied by dynamic regional brain imaging in nonhuman primates by with SPECT or PET. We estimate that four compounds per year will be imaged. The causes of Alzheimer's disease (AD) are still unclear, but postmortem examination of patient's brains reveal abundant senile plaques composed of amyloid-beta (A[unreadable]) peptides and neurofibrillary tangles formed by filaments of highly phosphorylated tau protein. Thus, a radiotracer that bound specifically to A[unreadable] protein would provide an in vivo measure of this process and would find application in the study, diagnosis, and treatment of psychiatric disorders. In this application we proposed to develop a selective compound to quantify these plaques in human. [unreadable] [unreadable] [unreadable] [unreadable]